There is an ongoing need for compositions and methods for altering the lifespan of eukaryotic cells and organisms. Dietary restriction (DR), also referred to as caloric restriction, has been proposed as one mechanism for altering the lifespan of eukaryotes. DR involves underfeeding short of malnutrition. DR regimens extend lifespan in eukaryotes from yeast to mammals by conserved genetic mechanisms, and delay the onset of age-related diseases such as diabetes, metabolic disorders, neurodegenerative diseases, cardiovascular diseases and cancer (Masoro, E, J. 2005. Overview of caloric restriction and ageing. Mech. Age. Dev. 126:913-922.; Morley, J. E., Chahla, E. Alkaade, S. (2010) Antiaging, longevity and caloric restriction. Curr. Opin. Clin, Nutr. Metab. Care. 13:40-45.). Optimal DR diets have not been determined for any organism, and it is likely that reducing specific nutrients within these diets, such as certain amino acids, may play disproportionate roles in achieving the full therapeutic benefits of DR. DR mimetics are a hypothetical class of drug that induce the beneficial affects of DR without altering diet.
Though the cellular mechanism(s) through which DR regimens exert their benefits are not well understood, their potential therapeutic value to humans has generated considerable interest. Studies have been extended to primates where it was shown that Rhesus monkeys kept for years on a DR regimen exhibit significantly fewer age-related diseases than animals kept on a normal diet (Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., Allison, D. B., Cruzen, C., Simmons, H. A., Kemnitz, J. W., Weindruch, R. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 325:201-4.).
DR likely acts at least in part by reducing levels of deleterious reactive oxygen species (ROS). The long-term production of ROS in various tissues leads to chronic inflammation, tissue damage and, ultimately, age-related diseases (Chung, H. Y. et al. 2009. Molecular Inflammation Underpinnings of aging and age-related diseases. Ageing Research Rev. 8:18-30.). It is likely that many, if not all, bona fide DR mimetics will have anti-inflammatory activity. In contrast, not all anti-inflammatory drugs will exhibit DR mimetic activity. Thus DR mimetics may be active against any disease or disorder that has an inflammatory component, including those not necessarily associated with aging. However, there remains an ongoing and unmet need for DR mimetics for use in extending life span and for therapy and/or prophylaxis of inflammation.